Bartonella was first described as a cause of endocarditis in two separate reports in 1993 and subsequently has been appreciated as a significant cause of ‘culture-negative’ endocarditis.

Blood culture-negative endocarditis (BCNE) is a term used in the cardiology literature to describe cases of infective endocarditis for which there is no bacterial growth in three independent blood samples cultured on standard aerobic media after seven days of incubation and subculturing.

Six Bartonella species have been reported to cause infective endocarditis in humans: B. quintana, B. henselae, B. elizabethae, B. vinsonii, B. koehlerae and B. alsatica. More than 95% of the cases, however, have involved either B. quintana or B. henselae.

Bartonella infection develops more commonly in patients with HIV infection and advanced immune suppression. Ownership of cats and underlying heart valve damage are predisposing factors for B. henselae endocarditis. Bartonella causes a wide spectrum of clinical infections, ranging in severity from asymptomatic or mild febrile illness to endocarditis.

Thirty-eight year old female

We present a case report of a 38-year-old female, who presented to the emergency department with complaints of generalised lethargy, anorexia, weight loss, exertional shortness of breath and intermittent chest pain for the past three months. She had a history of hypertension and clipping of two aneurysms in both middle cerebral arteries. Medications included amlodipine and perindopril. She was a 30-pack-year smoker and drank alcohol in moderation. She was living with her partner, two daughters and a dog. She denied use of any recreational drugs and had not travelled abroad in the past two years.

Initial examination revealed low-grade pyrexia, 37.8ºC, diastolic murmur at aortic area and mild splenomegaly. 

Lab evaluation showed the following values: 

• Hb 10
• WBC 3.1
• Neut 2.1
• Plt 285
• ESR 103
• CRP 57
• Urea 4.9
• Creatinine 101
• Sodium 134
• Potassium 4.5 and normal coagulation profile. 

Glucose, calcium magnesium and phosphate levels were normal. Three sets of blood cultures were sent. Electrocardiogram (ECG) was normal and chest X-ray was also normal.

The patient was started on benzylpenicillin, flucloxacillin and gentamycin for provisional diagnosis of sub-acute bacterial endocarditis (SBE). Transthoracic echocardiogram the following morning showed aortic valve thickening, suspicious for vegetation, with moderate aortic regurgitation and normal LV function.

Abdominal ultrasound: enlarged spleen

Ultrasound abdomen showed enlarged spleen with normal other viscera. The patient received the same antibiotics for one week. Gentamycin was stopped after one week. Serology for atypical organism for SBE was also sent. 

Four weeks after continuous antibiotics, the patient improved clinically and laboratory parameters for inflammation also improved. 

During week five, the patient developed a sore throat and started to spike high-grade fever. Flucloxacillin was switched to vancomycin. Multiple sets of blood cultures, which were taken before and during therapy, remained negative for any bacterial growth. 

During the fifth week, B. henselae serology came back as positive while Brucella and Coxiella were negative. At this stage vancomycin was stopped and doxycycline and rifampicin were started. Mantoux test and ASO titers were negative. Anti-nuclear antibody/anti-neutrophil cytoplasmic antibody (ANA/ANCA) were negative with normal C3 and C4 levels. TTE was repeated which showed vegetation on aortic valve, with a suspicion of aortic route abscess. 

Transoesophageal ECHO was performed the following morning, which showed aortic valve vegetation without significant valve destruction or abscess. The patient completed six weeks of antibiotics and was discharged on a further six weeks of doxycycline and rifampicin. She was reviewed in the clinic frequently and remained clinically well for the next 10 weeks.

The patient was readmitted with complaints of fever and shortness of breath after 10 weeks of stopping antibiotics. Ceftriaxone, gentamycin and doxycycline were restarted. TTE showed vegetations on both cusps of aortic valve with moderate aortic insufficiency (AI). 

Six weeks of antibiotics were completed, while making arrangements for aortic valve replacement. Blood cultures remained persistently negative for any bacterial growth. Finally, seven months after her first diagnosis of SBE, the patient was transferred to the Mater Hospital in Dublin for aortic valve replacement.

Polymerase chain reaction (PCR) confirmed the presence of B. henselae in the vegetation. The patient’s overall clinical condition improved soon after the valve replacement. During the second post-operative week, she developed a post-pericardiotomy syndrome-related pericardial effusion that was managed medically and did not require invasive intervention. 

The patient was then discharged, and she completed a six-week course of oral azithromycin and levofloxacin at home. Six months after the surgery, the patient remained clinically stable.

Discussion

Culture-negative endocarditis remains a diagnostic and therapeutic problem, accounting for 5-30% of all endocarditis cases. More recently, Bartonella has been recognised as an important cause of culture-negative endocarditis.¹ Three Bartonella species, in particular, are known to cause infective endocarditis: B. henselae, B. quintana, and B. elizabethae. 

The Gram-negative rod (white circle), which is indicative of B. henselae, was identified after a positive Warthin-Starry stain.

Blood cultures from patients with Bartonella endocarditis require prolonged incubation before they become positive (if they become positive at all), and they are not considered the optimal diagnostic test for this organism. 

The histopathology of cardiac valvular tissue may contribute to the aetiological diagnosis of Bartonella endocarditis when serology or molecular techniques are not available. Warthin-Starry silver staining may, in some instances, reveal the organisms as dark-stained bacteria. Immunofluorescence assays (IFA) and enzyme-linked immunosorbent assay are the two serologic methods currently used to diagnose Bartonella infections.

Current serological tests do not reliably distinguish B. quintana antibody responses from B. henselae. Cross-reactivity between Bartonella species and other organisms, including Coxiella burnetii² and Chlamydia trachomatis species,³ has been reported. PCR has been a very useful technique for demonstrating Bartonella DNA in cardiac valvular tissue, especially when fresh valvular tissue is used.⁴

The optimal antibiotic therapy for Bartonella endocarditis is unknown. First, the role of antibiotic therapy is limited by the fact that most Bartonella endocarditis patients have undergone valve replacement despite intravenous antimicrobial therapy.^3,4 Second, the literature consists mostly of series of case reports and does not show use of a consistent antibiotic therapy regimen. 

Finally, it should be noted that Bartonella-induced endocarditis usually results in extensive valve damage requiring replacement.^3,6 A study investigating the bactericidal activity of antibiotics against Bartonella species in vitro found only aminoglycosides to be bactericidal against B. henselae.⁷ An antibiotic regimen for Bartonella endocarditis consisting of gentamycin and either ceftriaxone or doxycycline, has been suggested.⁸ Based on experience with other Bartonella infections, the use of macrolides (erythromycin, azithromycin and clarithromycin) is a reasonable option but, given their bacteriostatic nature, the addition of a bactericidal agent is recommended.

References

1. Breathnach AS, Hoare JM, Eykyn SJ. Culture-negative endocarditis: contribution of Bartonella infections. Heart 1997; 77: 474-476 
2. Cooper MD, Hollingdale MR, Vinson JW, Costa J. A passive hemagglutination test for the diagnosis of trench fever due to Rochalimaea quintana. J Infect Dis 1976; 134: 605-609
3. Drancourt M, Mainardi J L, Brouqui P et al. Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med 1995; 332: 419-423
4. Raoult D, Fournier PE, Drancourt M et al. Diagnosis of 22 new cases of Bartonella endocarditis. Ann Intern Med 1996; 125: 646-652
5. Breitschwerdt EB, Kordick DL, Malarkey DE et al. Endocarditis in a dog due to infection with a novel Bartonella subspecies. J Clin Microbiol 1995; 33: 154-160
6. Daly JS, Worthington MG, Brenner DJ et al. Rochalimaea elizabethae sp. nov. isolated from a patient with endocarditis. J Clin Microbiol 1993; 31: 872-881
7. Musso D, Drancourt M, Raoult D. Lack of bactericidal effect of antibiotics except aminoglycosides on Bartonella (Rochalimaea) henselae. J Antimicrob Chemother 1995; 36: 101-108
8. Maurin M, Raoult D. Bartonella (Rochalimaea) quintana infections. Clin Microbiol Rev 1996; 9: 273-292